The purpose of this project is to study the action of diphtheria toxin at the cellular and molecular level. Our major objectives include: 1) Determination of the presence and activity of toxin-specific receptor sites and determination of the mechanism by which diphtheria toxin is activated and enters cells; 2) Determination of the cellular and molecular basis for the resistance to diphtheria toxin found in some cells and animal species; 3) Elucidation of steps which lead to inhibition of protein synthesis in intoxicated cells; and 4) Extension of our study to include the interaction of other biologically active agents with cells. Investigations will be conducted using cultured mammalian cells and cell-free systems. A unique opportunity for investigation of both sensitivity and resistance to toxin is presented by isolation in our laboratory of toxin-resistant strains of human and non-human cells which are blocked at different steps in the intoxication process, some of which are resistant to certain viruses, as well.